title: JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats.
abstract: Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kohro
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsujikawa
authors.forename: Junko
authors.initials: J
authors.lastname: Kitano
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D049109:Cell Proliferation; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013127:Spinal Nerves / Q000293:injuries* / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D053612:Janus Kinases